tbuckley/cabot-search huggingface dataset:
Prediction of breast cancer risk for sisters of women attending screening
Authors: Xinhe Mao, Wei He, Mikael Eriksson, Linda S Lindström, Natalie Holowko, Svetlana Bajalica-Lagercrantz, Mattias Hammarström, Felix Grassmann, Keith Humphreys, Douglas Easton, Per Hall, Kamila Czene
Journal: JNCI Journal of the National Cancer Institute (2023)

Abstract Background Risk assessment is important for breast cancer prevention and early detection. We aimed to examine whether common risk factors, mammographic features, and breast cancer risk prediction scores of a woman were associated with breast cancer risk for her sisters. Methods We included 53 051 women from the Karolinska Mammography Project for Risk Prediction of Breast Cancer (KARMA) study. Established risk factors were derived using self-reported questionnaires, mammograms, and single nucleotide polymorphism genotyping. Using the Swedish Multi-Generation Register, we identified 32 198 sisters of the KARMA women (including 5352 KARMA participants and 26 846 nonparticipants). Cox models were used to estimate the hazard ratios of breast cancer for both women and their sisters, respectively. Results A higher breast cancer polygenic risk score, a history of benign breast disease, and higher breast density in women were associated with an increased risk of breast cancer for both women and their sisters. No statistically significant association was observed between breast microcalcifications and masses in women and breast cancer risk for their sisters. Furthermore, higher breast cancer risk scores in women were associated with an increased risk of breast cancer for their sisters. Specifically, the hazard ratios for breast cancer per 1 standard deviation increase in age-adjusted KARMA, Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA), and Tyrer-Cuzick risk scores were 1.16 (95% confidence interval [CI] = 1.07 to 1.27), 1.23 (95% CI = 1.12 to 1.35), and 1.21 (95% CI = 1.11 to 1.32), respectively. Conclusion A woman’s breast cancer risk factors are associated with her sister’s breast cancer risk. However, the clinical utility of these findings requires further investigation.
Translocation of IGF-1R in endoplasmic reticulum enhances SERCA2 activity to trigger Ca2+ER perturbation in hepatocellular carcinoma
Authors: Yanan Li, Keqin Li, Ting Pan, Qiaobo Xie, Yuyao Cheng, Xinfeng Wu, Rui Xu, Xiaohui Liu, Li Liu, Jiangming Gao, Wenmin Yuan, Xianjun Qu, Shuxiang Cui
Journal: Acta Pharmaceutica Sinica B (2023)

The well-known insulin-like growth factor 1 (IGF1)/IGF-1 receptor (IGF-1R) signaling pathway is overexpressed in many tumors, and is thus an attractive target for cancer treatment. However, results have often been disappointing due to crosstalk with other signals. Here, we report that IGF-1R signaling stimulates the growth of hepatocellular carcinoma (HCC) cells through the translocation of IGF-1R into the ER to enhance sarco-endoplasmic reticulum calcium ATPase 2 (SERCA2) activity. In response to ligand binding, IGF-1Rβ is translocated into the ER by β-arrestin2 (β-arr2). Mass spectrometry analysis identified SERCA2 as a target of ER IGF-1Rβ. SERCA2 activity is heavily dependent on the increase in ER IGF-1Rβ levels. ER IGF-1Rβ phosphorylates SERCA2 on Tyr990 to enhance its activity. Mutation of SERCA2-Tyr990 disrupted the interaction of ER IGF-1Rβ with SERCA2, and therefore ER IGF-1Rβ failed to promote SERCA2 activity. The enhancement of SERCA2 activity triggered Ca2+ER perturbation, leading to an increase in autophagy. Thapsigargin blocked the interaction between SERCA2 and ER IGF-1Rβ and therefore SERCA2 activity, resulting in inhibition of HCC growth. In conclusion, the translocation of IGF-1R into the ER triggers Ca2+ER perturbation by enhancing SERCA2 activity through phosphorylating Tyr990 in HCC.
Modulation of T cells by tryptophan metabolites in the kynurenine pathway
Authors: Trevor W. Stone, Richard O. Williams
Journal: Trends in Pharmacological Sciences (2023)

Lymphocytes maturing in the thymus (T cells) are key factors in adaptive immunity and the regulation of inflammation. The kynurenine pathway of tryptophan metabolism includes several enzymes and compounds that can modulate T cell function, but manipulating these pharmacologically has not achieved the expected therapeutic activity for the treatment of autoimmune disorders and cancer. With increasing knowledge of other pathways interacting with kynurenines, the expansion of screening methods, and the application of virtual techniques to understanding enzyme structures and mechanisms, details of interactions between kynurenines and other pathways are being revealed. This review surveys some of these alternative approaches to influence T cell function indirectly via the kynurenine pathway and summarizes the most recent work on the development of compounds acting directly on the kynurenine pathway.
Isoliquiritigenin inhibits circ0030018 to suppress glioma tumorigenesis via the miR‐1236/HER2 signaling pathway
Authors: Aiqun Liu, Baohong Jiang, Cailu Song, Qizhi Zhong, Yufan Mo, Ruiqin Yang, Ciyu Chen, Cheng Peng, Fu Peng, Hailin Tang
Journal: MedComm (2023)

In the central nervous system diseases, glioma is one of the most common malignancies around the world. Despite the recent improvements in therapies for glioma, the prognosis of some high-risk glioma remains poor. In glioma, isoliquiritigenin (ISL) is reported to have antioxidative and antitumor activities. However, the potential mechanisms between ISL and circle RNAs (circRNAs) in the glioma tumorigenesis process have not yet been reported. Here, we treated glioma cells with ISL, and circRNA expression levels were detected. Circ0030018 was found significantly downregulated by ISL. Therefore, we explored circ0030018 expression profiles and functions in glioma, finding that circ0030018 was evidently overexpressed in glioma cell lines. Colony formation, CCK-8, and transwell assay made clear that circ0030018 silencing dramatically cut down glioma growth and invasion. Moreover, ROS level was detected to find that circ0030018 silence remarkably enhanced cell oxidative stress in glioma. Mechanism studies were conducted to investigate the underlying basis of circ0030018 function in glioma, unveiling that circ0030018 realized its functions partially through the miR-1236/HER2 signaling in glioma. In conclusion, our study investigated the roles and mechanisms of the ISL on the circ0030018/miR-1236/HER2 pathway in glioma tumorigenesis and progression. Circ0030018 could act as the prospective biologic signature or therapeutic target for glioma.
Continence Problems and Mental Health in Adolescents from a UK Cohort
Authors: Katie Gordon, Naomi Warne, Jon Heron, Alexander von Gontard, Carol Joinson
Journal: European Urology (2023)

Adolescents with continence problems experience unique threats to their psychological well-being, but long-term mental health sequelae are unknown.To examine prospective relationships between incontinence/lower urinary tract symptoms (LUTS) and mental health problems in young people.A prospective cohort study of young people (n = 7332: 3639 males and 3693 females) from a population-based sample was conducted.We estimated the association between incontinence/LUTS and mental health outcomes using multivariable regression models adjusted for sex, socioeconomic position, developmental level, intelligence quotient, stressful life events, maternal psychopathology, body mass index, and emotional/behavioural problems.Daytime wetting and voiding postponement showed the greatest number of associations with mental health problems. All incontinence subtypes/LUTS were associated with increased odds of generalised anxiety disorder (eg, odds ratio for daytime wetting = 3.01, 95% confidence interval [1.78, 5.09], p < 0.001) and/or higher anxiety scores. There was also evidence of associations with common mental disorder (eg, voiding postponement: 1.88 [1.46, 2.41], p < 0.001), depression (eg, urgency: 1.94 [1.19, 3.14], p = 0.008), depressive symptoms (eg, daytime wetting: 1.70 [1.13, 2.56], p = 0.01), self-harm thoughts (eg, voiding postponement: 1.52 [1.16, 1.99], p = 0.003), and disordered eating (eg, nocturia 1.72 [1.27, 2.34], p = 0.001). We are unable to generalise our results to minority ethnic groups, less affluent populations, and non-UK samples.Young people with incontinence/LUTS are at an increased risk of mental health problems. Further research is needed to establish the direction of causality.We looked at the association between continence problems and mental health outcomes in young people from a large population-based cohort. Young people with continence problems at the age of 14 yr were more likely to suffer from a range of mental health problems at the age of 18 yr, including common mental disorder, depression, anxiety, self-harm thoughts, and disordered eating. Paediatric continence clinics should address the mental health needs of young people and provide clear and effective care pathways to child and adolescent mental health services.
Generating synthetic mixed-type longitudinal electronic health records for artificial intelligent applications
Authors: Jin Li, Benjamin J. Cairns, Jingsong Li, Tingting Zhu
Journal: npj Digital Medicine (2023)

The recent availability of electronic health records (EHRs) have provided enormous opportunities to develop artificial intelligence (AI) algorithms. However, patient privacy has become a major concern that limits data sharing across hospital settings and subsequently hinders the advances in AI. Synthetic data, which benefits from the development and proliferation of generative models, has served as a promising substitute for real patient EHR data. However, the current generative models are limited as they only generate single type of clinical data for a synthetic patient, i.e., either continuous-valued or discrete-valued. To mimic the nature of clinical decision-making which encompasses various data types/sources, in this study, we propose a generative adversarial network (GAN) entitled EHR-M-GAN that simultaneously synthesizes mixed-type timeseries EHR data. EHR-M-GAN is capable of capturing the multidimensional, heterogeneous, and correlated temporal dynamics in patient trajectories. We have validated EHR-M-GAN on three publicly-available intensive care unit databases with records from a total of 141,488 unique patients, and performed privacy risk evaluation of the proposed model. EHR-M-GAN has demonstrated its superiority over state-of-the-art benchmarks for synthesizing clinical timeseries with high fidelity, while addressing the limitations regarding data types and dimensionality in the current generative models. Notably, prediction models for outcomes of intensive care performed significantly better when training data was augmented with the addition of EHR-M-GAN-generated timeseries. EHR-M-GAN may have use in developing AI algorithms in resource-limited settings, lowering the barrier for data acquisition while preserving patient privacy.
Unraveling the serial glycosylation in the biosynthesis of steroidal saponins in the medicinal plant Paris polyphylla and their antifungal action
Authors: Yuegui Chen, Qin Yan, Yunheng Ji, Xue Bai, Desen Li, Rongfang Mu, Kai Guo, Minjie Yang, Yang Tao, Jonathan Gershenzon, Yan Liu, Shenghong Li
Journal: Acta Pharmaceutica Sinica B (2023)

Sugar–sugar glycosyltransferases play important roles in constructing complex and bioactive saponins. Here, we characterized a series of UDP-glycosyltransferases responsible for biosynthesizing the branched sugar chain of bioactive steroidal saponins from a widely known medicinal plant Paris polyphylla var. yunnanensis. Among them, a 2′-O-rhamnosyltransferase and three 6′-O-glucosyltrasferases catalyzed a cascade of glycosylation to produce steroidal diglycosides and triglycosides, respectively. These UDP-glycosyltransferases showed astonishing substrate promiscuity, resulting in the generation of a panel of 24 terpenoid glycosides including 15 previously undescribed compounds. A mutant library containing 44 variants was constructed based on the identification of critical residues by molecular docking simulations and protein model alignments, and a mutant UGT91AH1Y187A with increased catalytic efficiency was obtained. The steroidal saponins exhibited remarkable antifungal activity against four widespread strains of human pathogenic fungi attributed to ergosterol-dependent damage of fungal cell membranes, and 2′-O-rhamnosylation appeared to correlate with strong antifungal effects. The findings elucidated the biosynthetic machinery for their production of steroidal saponins and revealed their potential as new antifungal agents.
Lack of Benefit of Methotrexate in Severe, Steroid-Dependent Asthma
Authors: Serpil C. Erzurum, Jonathan A. Leff, Judith Evans Cochran, Lynn M. Ackerson, Stanley J. Szefler, Richard J. Martin, Gary R. Cott
Journal: Annals of Internal Medicine (1991)

Objective: To determine the effect of low-dose methotrexate in asthmatic patients on steroid use, asthma symptom scores, pulmonary function, airway reactivity, blood cellular components, and immunoglobulin E levels. Design: A randomized, double-blind, parallel, placebocontrolled, 13-week clinical trial with follow-up of patients in an open trial of methotrexate at the conclusion of the double-blind study. Setting: An asthma care outpatient clinic. Patients: From February 1988 to March 1990, 19 patients with severe, steroid-dependent asthma were enrolled in the study. Two of these patients were excluded from analysis. Interventions: Patients were administered methotrexate or placebo intramuscularly, to assure complete absorption, once weekly during the 13-week study. Results: Patients on methotrexate and placebo both significantly decreased their steroid dose by 39.6% (95% CI, 25.1% to 54.1%, P = 0.001) and 40.2% (CI, 17.9% to 67.4%, P = 0.003), respectively. Pulmonary function did not differ significantly between the methotrexate and placebo groups. In addition, airway reactivity and symptom scores were unchanged on methotrexate or placebo. No significant toxicities were seen during the course of the 13-week blinded study, but one patient on methotrexate and prednisone in the follow-up period developed Pneumocystis carinii pneumonia and died. Despite continuing methotrexate for up to 1 year, and increasing methotrexate to 30 mg weekly, no significant benefit of methotrexate on asthma control could be shown. Conclusion: Our study does not support the use of methotrexate in the treatment of severe asthma.
Bispecific antibodies for targeted delivery of anti-cancer therapeutic agents: A review
Authors: Adilet Beishenaliev, Yean Leng Loke, Sook Jing Goh, Hui Nee Geo, Malar Mugila, Misni Misran, Lip Yong Chung, Lik Voon Kiew, Steve Roffler, Yin Yin Teo
Journal: Journal of Controlled Release (2023)
Graphdiyne nanoplatforms for photothermal-ferroptosis combination therapy against glioblastoma
Authors: Ling-Xiao Zhao, Zhi-Qiang Gong, Qi Zhang, Da-Long He, Ri-Le Ge, Jin Meng, Hang Ren, Yong-Gang Fan, Zhan-You Wang
Journal: Journal of Controlled Release (2023)
Genome-wide discovery of genetic loci that uncouple excess adiposity from its comorbidities
Authors: Lam O. Huang, Alexander Rauch, Eugenia Mazzaferro, Michael Preuss, Stefania Carobbio, Cigdem S. Bayrak, Nathalie Chami, Zhe Wang, Ursula M. Schick, Nancy Yang, Yuval Itan, Antonio Vidal-Puig, Marcel den Hoed, Susanne Mandrup, Tuomas O. Kilpeläinen, Ruth J. F. Loos
Journal: Nature Metabolism (2021)
Heart-derived collagen promotes maturation of engineered heart tissue
Authors: Hidenori Tani, Eiji Kobayashi, Shinomi Yagi, Keisuke Tanaka, Kotaro Kameda-Haga, Shinsuke Shibata, Nobuko Moritoki, Kaworu Takatsuna, Taijun Moriwaki, Otoya Sekine, Tomohiko C Umei, Yuika Morita, Yusuke Soma, Yoshikazu Kishino, Hideaki Kanazawa, Jun Fujita, Shunji Hattori, Keiichi Fukuda, Shugo Tohyama
Journal: Biomaterials (2023)

Although the extracellular matrix (ECM) plays essential roles in heart tissue engineering, the optimal ECM components for heart tissue organization have not previously been elucidated. Here, we focused on the main ECM component, fibrillar collagen, and analyzed the effects of collagens on heart tissue engineering, by comparing the use of porcine heart-derived collagen and other organ-derived collagens in generating engineered heart tissue (EHT). We demonstrate that heart-derived collagen induces better contraction and relaxation of human induced pluripotent stem cell-derived EHT (hiPSC-EHT) and that hiPSC-EHT with heart-derived collagen exhibit more mature profiles than those with collagens from other organs. Further, we found that collagen fibril formation and gel stiffness influence the contraction, relaxation, and maturation of hiPSC-EHT, suggesting the importance of collagen types III and type V, which are relatively abundant in the heart. Thus, we demonstrate the effectiveness of organ-specific collagens in tissue engineering and drug discovery.
Wnt-β-catenin in hepatobiliary homeostasis, injury, and repair
Authors: Kari Nejak-Bowen, Satdarshan P. Monga
Journal: Hepatology (2023)

Wnt-β-catenin signaling has emerged as an important regulatory pathway in the liver, playing key roles in zonation and mediating contextual hepatobiliary repair after injuries. In this review, we will address the major advances in understanding the role of Wnt signaling in hepatic zonation, regeneration, and cholestasis-induced injury. We will also touch on some important unanswered questions and discuss the relevance of modulating the pathway to provide therapies for complex liver pathologies that remain a continued unmet clinical need.
Targeting the p53 signaling pathway in cancers: Molecular mechanisms and clinical studies
Authors: Jinze Shen, Qurui Wang, Yunan Mao, Wei Gao, Shiwei Duan
Journal: MedComm (2023)

Tumor suppressor p53 can transcriptionally activate downstream genes in response to stress, and then regulate the cell cycle, DNA repair, metabolism, angiogenesis, apoptosis, and other biological responses. p53 has seven functional domains and 12 splice isoforms, and different domains and subtypes play different roles. The activation and inactivation of p53 are finely regulated and are associated with phosphorylation/acetylation modification and ubiquitination modification, respectively. Abnormal activation of p53 is closely related to the occurrence and development of cancer. While targeted therapy of the p53 signaling pathway is still in its early stages and only a few drugs or treatments have entered clinical trials, the development of new drugs and ongoing clinical trials are expected to lead to the widespread use of p53 signaling-targeted therapy in cancer treatment in the future. TRIAP1 is a novel p53 downstream inhibitor of apoptosis. TRIAP1 is the homolog of yeast mitochondrial intermembrane protein MDM35, which can play a tumor-promoting role by blocking the mitochondria-dependent apoptosis pathway. This work provides a systematic overview of recent basic research and clinical progress in the p53 signaling pathway and proposes that TRIAP1 is an important therapeutic target downstream of p53 signaling.
IGF2BP1 induces neuroblastoma via a druggable feedforward loop with MYCN promoting 17q oncogene expression
Authors: Sven Hagemann, Danny Misiak, Jessica L. Bell, Tommy Fuchs, Marcell I. Lederer, Nadine Bley, Monika Hämmerle, Ehab Ghazy, Wolfgang Sippl, Johannes H. Schulte, Stefan Hüttelmaier
Journal: Molecular Cancer (2023)

Abstract Background Neuroblastoma is the most common solid tumor in infants accounting for approximately 15% of all cancer-related deaths. Over 50% of high-risk neuroblastoma relapse, emphasizing the need of novel drug targets and therapeutic strategies. In neuroblastoma, chromosomal gains at chromosome 17q, including IGF2BP1 , and MYCN amplification at chromosome 2p are associated with adverse outcome. Recent, pre-clinical evidence indicates the feasibility of direct and indirect targeting of IGF2BP1 and MYCN in cancer treatment. Methods Candidate oncogenes on 17q were identified by profiling the transcriptomic/genomic landscape of 100 human neuroblastoma samples and public gene essentiality data. Molecular mechanisms and gene expression profiles underlying the oncogenic and therapeutic target potential of the 17q oncogene IGF2BP1 and its cross-talk with MYCN were characterized and validated in human neuroblastoma cells, xenografts and PDX as well as novel IGF2BP1/MYCN transgene mouse models. Results We reveal a novel, druggable feedforward loop of IGF2BP1 (17q) and MYCN (2p) in high-risk neuroblastoma. This promotes 2p/17q chromosomal gains and unleashes an oncogene storm resulting in fostered expression of 17q oncogenes like BIRC5 (survivin). Conditional, sympatho-adrenal transgene expression of IGF2BP1 induces neuroblastoma at a 100% incidence. IGF2BP1-driven malignancies are reminiscent to human high-risk neuroblastoma, including 2p/17q-syntenic chromosomal gains and upregulation of Mycn, Birc5, as well as key neuroblastoma circuit factors like Phox2b. Co-expression of IGF2BP1/MYCN reduces disease latency and survival probability by fostering oncogene expression. Combined inhibition of IGF2BP1 by BTYNB, MYCN by BRD inhibitors or BIRC5 by YM-155 is beneficial in vitro and, for BTYNB, also. Conclusion We reveal a novel, druggable neuroblastoma oncogene circuit settling on strong, transcriptional/post-transcriptional synergy of MYCN and IGF2BP1. MYCN/IGF2BP1 feedforward regulation promotes an oncogene storm harboring high therapeutic potential for combined, targeted inhibition of IGF2BP1, MYCN expression and MYCN/IGF2BP1-effectors like BIRC5.
Discovery of highly immunogenic spleen-resident FCGR3+CD103+ cDC1s differentiated by IL-33-primed ST2+ basophils
Authors: Myeong-Ho Kang, JungHyub Hong, Jinjoo Lee, Min-Suk Cha, Sangho Lee, Hye-Young Kim, Sang-Jun Ha, Yong Taik Lim, Yong-Soo Bae
Journal: Cellular and Molecular Immunology (2023)

Abstract Recombinant interleukin-33 (IL-33) inhibits tumor growth, but the detailed immunological mechanism is still unknown. IL-33-mediated tumor suppression did not occur in Batf3 −/− mice, indicating that conventional type 1 dendritic cells (cDC1s) play a key role in IL-33-mediated antitumor immunity. A population of CD103 + cDC1s, which were barely detectable in the spleens of normal mice, increased significantly in the spleens of IL-33-treated mice. The newly emerged splenic CD103 + cDC1s were distinct from conventional splenic cDC1s based on their spleen residency, robust effector T-cell priming ability, and surface expression of FCGR3. DCs and DC precursors did not express Suppressor of Tumorigenicity 2 (ST2). However, recombinant IL-33 induced spleen-resident FCGR3 + CD103 + cDC1s, which were found to be differentiated from DC precursors by bystander ST2 + immune cells. Through immune cell fractionation and depletion assays, we found that IL-33-primed ST2 + basophils play a crucial role in the development of FCGR3 + CD103 + cDC1s by secreting IL-33-driven extrinsic factors. Recombinant GM-CSF also induced the population of CD103 + cDC1s, but the population neither expressed FCGR3 nor induced any discernable antitumor immunity. The population of FCGR3 + CD103 + cDC1s was also generated in vitro culture of Flt3L-mediated bone marrow-derived DCs (FL-BMDCs) when IL-33 was added in a pre-DC stage of culture. FL-BMDCs generated in the presence of IL-33 (FL-33-DCs) offered more potent tumor immunotherapy than control Flt3L-BMDCs (FL-DCs). Human monocyte-derived DCs were also more immunogenic when exposed to IL-33-induced factors. Our findings suggest that recombinant IL-33 or an IL-33-mediated DC vaccine could be an attractive protocol for better tumor immunotherapy.
RAS‐targeted cancer therapy: Advances in drugging specific mutations
Authors: Cen Liu, Danyang Ye, Hongliu Yang, Xu Chen, Zhijun Su, Xia Li, Mei Ding, Yonggang Liu
Journal: MedComm (2023)

Rat sarcoma (RAS), as a frequently mutated oncogene, has been studied as an attractive target for treating RAS-driven cancers for over four decades. However, it is until the recent success of kirsten-RAS (KRAS)